Despite significant advances in therapy, cardiovascular disease remains the single most common cause of morbidity and mortality in the developed world. Thus, prevention of cardiovascular disorders such as myocardial infarction and stroke is an area of major public health importance. Currently, several risk factors for future cardiovascular disorders have been described and are in wide clinical use in the detection of individuals at high risk. Such screening tests include evaluations of total and HDL cholesterol levels. However, a large number of cardiovascular disorders occur in individuals with apparently low to moderate risk profiles, and our ability to identify such patients is limited. Moreover, accumulating data suggests that the beneficial effects of certain preventive and therapeutic treatments for patients at risk for or known to have cardiovascular disorders differs in magnitude among different patient groups. At this time, however, data describing diagnostic tests to determine whether certain therapies can be expected to be more or less effective are lacking.
Certain cardiovascular disorders, such as myocardial infarction and ischemic stroke, are associated with atherosclerosis. The mechanism of atherosclerosis is not well understood. CD40 ligand (also known as CD40L, CD154, and/or gp39) is a 261 amino acid, type II transmembrane protein. One or more biologically active soluble forms of the molecule, collectively designated sCD40L, are produced by proteolytic cleavage of the full-length form, which may occur intracellularly or on the cell surface.
CD40L is a multipotent immunomodulator that together with its receptor, CD40, are expressed on a broad variety of cells including vascular endothelial (EC) and smooth muscle cells (SMC), mononuclear phagocytes (MØ), and platelets.
Engagement of the CD40 receptor on any of the foregoing cell types, reportedly triggers the expression of various pro-inflammatory mediators, such as the cytokines IL1, IL-6, IL-12, TNFα, or IFNγ, the chemokines IL-8, MCP-1, or RANTES, the adhesion molecules ICAM-1 or VCAM-1, the matrix metalloproteinases MMP-1/-2/-3/-7/-8/-9/-10/-11/-12/-13, as well as the procoagulant tissue factor. Expression of these pro-inflammatory mediators has been, reportedly, linked to the promotion of a wide array of pro-atherogenic functions in vitro. These observations have implicated CD40L in the various stages of atherogenesis.
Elevated levels of sCD40L have been described among patients with unstable angina. Further, concentrations of sCD40L in serum or other body fluids have been used to assess the immune, inflammatory, or malignant status of human patients. Such patients include patients suffering from systemic autoimmunity or inflammation, vascular diseases, viral diseases, or malignancies, or patients undergoing immunosuppressive therapy. These patients are not healthy individuals. Since levels of sCD40L increase during inflammation, it has been uncertain whether statistical associations observed in these prior studies of acutely ill or high-risk populations are causal, are due to short-term inflammatory changes or are due to interrelations with other risk factors, in particular, smoking and hyperlipidemia.
Elevated levels of markers of inflammation have been shown previously to be predictive of future adverse cardiovascular disorders. This has not previously been demonstrated for sCD40L, a mediator of certain aspects of inflammation although not conventionally regarded previously as a systemic marker of inflammation.